Highly expressed in rod and cone photoreceptor cells of the retina, visual pigments are G protein-coupled receptors (GPCRs) comprised of an opsin apo-protein combined with a universal chromophore, 11-cis-retinal through a protonated Schiff base. Upon absorption of a photon of light, the retinylidene chromophore is efficiently photoisomerized to an all-trans configuration with subsequent activation of the photoreceptor. Spontaneous hydrolysis of the Schiff base bond subsequently liberates all-trans-retinal from the opsin, but because visual pigments are densely packed at a local concentration up to 5 mM, an intense stream of photons can produce high levels of all-trans-retinal. At even low micromolar concentrations, this aldehyde is toxic, and primarily affects photoreceptor cells.
To restore photoreceptor sensitivity to light, a constant supply of 11-cis-retinal is required, and vertebrates employ a metabolic pathway called the retinoid (visual) cycle by which all trans retinal is enzymatically re-isomerized back to the 11-cis configuration. This process is facilitated by two non-redundant enzymes, namely lecithin:retinol acyltransferase (LRAT) and retinoid isomerase, a retinal pigmented epithelium-specific 65 kDa protein (RPE65) (FIG. 1). Retinylamine was the first described potent inhibitor of RPE65 discovered. But both enzymes employ retinylamine as a substrate. First retinylamine is retained in the eye by the action of LRAT that produces its amidated precursor, and then the resulting retinyl amide then is slowly hydrolyzed to evoke long-lasting suppression of retinoid isomerase activity.
An operative visual cycle is critical for sustaining continuous vision and maintaining the health of photoreceptor cells. Proper homeostasis of retinoid metabolism supports visual function under a variety of lighting conditions. However, certain environmental insults including prolonged exposure to intense light in combination with an unfavorable genetic background can exceed the adaptive capabilities of the visual cycle and thus compromise retinal function. A clinical example is Stargardt disease, an inherited form of juvenile macular degeneration that results in progressive vision loss associated with mutations in the photoreceptor-specific ATP binding cassette transporter (ABCA4) that causes a delay in all-trans-retinal clearance. The resulting increased concentrations of all-trans-retinal exert a direct cytotoxic effect on photoreceptors in addition to contributing to formation of side-products such as N-retinylidene-N-retinylethanolamine (A2E) and retinal dimer.